Despite the fact that the great majority of cases of diarrhea occur in children living in impoverished settings, the evidence for the safety and efficacy of probiotics is principally derived from the U.S. and Europe. The long term goal is to improve quality of evidence regarding the safety, efficacy, and mechanism of action of probiotics for the treatment of diarrhea in early childhood in a population living in extreme poverty, where diarrhea, enteropathy, and stunting are common, so that evidenced-based probiotic strategies may be designed. Approach: The work will be conducted through first performing a Phase 1 study in infants and then proceeding to conduct a Phase 2 Clinical Trial in a birth cohort in Peru. The successful completion of these studies will evaluate safety in this population and yield information on the efficacy of L. reuteri DSM 17938 for all cause diarrhea and diarrhea caused by Norovirus, Campylobacter, Giardia, and Enteroggerative E. coli. Innovative aspects include a design that allows for the evaluation of the cumulative effect of the administration of the product strain on each incident episode over the first two years of life on the cumulative burden of disease and linear growth. Integrated measures including intestinal inflammation, permeability, and systemic inflammation will be complemented by studies of the gut microbiome on sample subsets to contribute important new information on the changes in the host physiology and microbiota that can be associated with treatment with treatment with L. reuteri DSM 17938. The research team is composed of scientists with diverse backgrounds and extensive experience in clinical trials, longitudinal field studies with intensive surveillance, and enteric diseases in Peu that is well positioned to carry out the regulatory, field, and basic science project components described in this proposal.